Pentanedione derivatives

ABSTRACT

Compounds of the formula   WHEREIN R is a hydrogen atom or an alkyl having one to five carbon atoms and n is an integer of 1 to 3, are produced by subjecting a compound of the formula   WHEREIN R an n have the same meaning as above, to hydrogenation. The compounds are cholagogue agents.

United States Patent 1 Yokotani et al.

[1;] 3,708,540 51 Jan. 2, 1973 Pattison et al., J.' Org.

PENTANEDIONE DERIVATIVES Inventors: Hajime Yokotani, Osaka; Masuo VAppl. No.: 56,971

Foreign Application Priority Data July 21, 1969 Japan ..44/57562 vs. C].,.....260/590, 424/351 Int. Cl ..C07c 49/82 Field of Search ..260/590References Cited OTHER PUBLICATIONS Chem. 33 3) 1084-1087 PrimaryExaminer-Daniel D. Horwitz Attorney-Wenderoth, Lind & Ponack ABSTRACTCompounds of the formula COCHa wherein R is a hydrogen atom or an alkylhaving one to five carbon atoms and n is an integer of l to 3, areproduced by subjecting a compound of the formula ()(Hllla wherein R an nhave the same meaning as above, to hydrogenation. The compounds arecholagogue agents. a

1 Claim, No Drawings PENTANEDIONE DERIVATIVES coon;

wherein R is a hydrogen atom or a lower alkyl group and n is an integerof Ho 3.

The lower alkyl group represented by R in the formula (I) is exemplifiedby alkyl having one to five carbon atoms such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl,isoamyl, etc.. Where n stands for 2 and 3, R may be the same ordifferent.

The novel compounds (1) are produced, for instance, by'subjecting acompound represented by the formula Y doom COCH;

,wherein R and n have the same meaning as above, to

them palladium-carbon catalyst is most desirable.

Usually, the catalytichydrogenation reaction proceeds rapidly at roomtemperature in a suitable solvent, which may, for example, be any ofalcohols such as methanol, ethanol, etc., ethers/such as ethyl ether,dioxane, etc., hydrocarbons such as benzene, cyclohexane, etc., esterssuch as ethyl acetate etc., carboxylic acid such as acetic acid etc. andthe like. These solvents may be used in any combination or as a mixedsolvent with water.

From the reaction mixture thus obtained, the desired 3-benzyl-2,4-.pentanedione derivatives may be isolated in conventional manner suchas recrystallization, distillation and chromatography. 7

The starting material represented by the formula (11) is, prepared, forexample, by reacting a compound represented by. the general formula.

wherein R and n have the same meaning as above with acetylacetone in thepresence of an organic base such as pyridine and piperidine.

Pharmaceutical compositions containing one or more of the compounds ofthis invention can be prepared according to any per se conventionalmeans for the preparation of tablet, powder, capsule, liquid orinjection. r

The compounds of this invention have an effective cholagogic activityand are generally administered orally in a form of tablet, powder,capsule, liquid, etc., or by way of injection.

A typical effective dose of the compounds of this invention, whenadministered orally to human adult, is

usually about 0.1g to 5.0g a day, desirably 0.3g to 1.5g.

a day and when administered intravenously, is usually about 0.05g. to3.0g. per does. Of course, an increased or reduced dose is alsoeffective or symptoms.

The physiological activity of the compounds of this invention isdemonstrated in the following tests.

Test for Cholagogic Activity Each sample compound suspended with 5percent gumm arabic in physiological saline was administered orally torats (female, SD-JCL rat, weighing 200 i 10g, which was pentobarbitalanesthetized after 20 hours fast) at the dosage of mg./kg. The bile wascontinuously collected through a polyethylene cannula inserted into thecommon bile duct and its volume was measured according to the methoddescribed in H. Yokotani; Folia Pharmacologica Japonica 56, 1373-1386(1960). The results are shown in Table 1;

Samples: Y

1. 3-( 3 '-methoxy-4-hydroxybenzyl )-2,4-pentanedione 2.3-(4-hydroxybenzyl)-2,4-pentanedione v 3. l-phenylpropanol (produced andsold by Schering I Corp. under the tradename F elicur 4.p-hydroxyphenyl-salicylamide (produced by Yoshitomi Pharmaceutical Co.Ltd. and sold by Takeda Chemical 1nd. Ltd. under the tradename YoshicholBo Total outflow during 4 hours after the administration of testcompounds b Ratio of bile outflow (bile volume in 1-5 hours/bile volumein 0-1 hour in the control rats) C Bile outflow during 1 hour before theadministration-of compounds. +-H-: remarkably effective 13 1.0-H-:fairly effective 1.0 B 0.7 Y +zefiective 0.7 B 0.4

i E slightly efiective 0.4 B 2 0.3

ineffective 0.3 B

Test for acute toxicity Each compound suspended with 5 percent gummarabic in physiological saline was administered orally to mice (femaleICR-JCL mouse, 4 weeks in age, weighing 18 :t 2g.). Thus administeredmice were observed for 4 days to estimate LD value. The results areshown in Table 2.

TABLE 2 dose (mg/g.) LD

compound EXAMPLE 1 In 100 parts by volume of methanol is added 4.5 partsby weight of 3-(4-hydroxybenzylidene)-2,4-pentanedione. Under using 0.3part by weight of palladium-carbon as catalyst, the above mixture issubjected to catalytic hydrogenation at room temperature (23C) and underatmospheric pressure. After 1 hour, the reaction is complete withadsorption of 540 parts by volume of hydrogen. The catalyst is filteredoff, followed by washing with 80 parts by volume of methanol. Thewashing is combined with the filtrate. The solvent is distilled off,whereby 4.5 parts by weight of yellowish oily substance is obtained. 10Parts by volume of benzene is added to the oily substance, and themixture is stirred, whereby 3.6 parts by weight of3-(4-hydroxybenzyl)-2,4-pentanedione is obtained as crystals. Thecrystals are recrystallized from hot benzene to give faintly yellowishplaty crystals melting at 90-9 1C.

Elementary analysis:

Calculated for c u o Found C 70.09 H 6.93

EXAMPLE 2 In 200 parts by volume of methanol is added 7 parts by weightof 3-(3'-methoxy-4-hydroxybenzylidine)- 2,4-pentanedione. Using 0.5 partby weight of palladium-carbon (5 percent), the mixture is subjected tocatalytic hydrogenation under the same conditions as in Example 1. After80 minutes, the reaction is complete with absorption of 770 parts byvolume of hydrogen. The reaction mixture is filtered, and the filtrateis concentrated. To the residue is added a small amount of ethylacetate, and the mixture is kept standing, whereby colorless crystals of3-(3-methoxy-4- hydroxybenzyl)-2,4-pentanedione and obtained. Afterseparating the crystals by filtration, the crystals are washed with 4parts by weight of ethyl acetate. The washing is combined with thefiltrate, andthe mixture is concentrated, whereby additional 0.6 part byweight of crystals are obtained. Recrystallization from aqueous alcoholgives colorless platy crystals melting at 75C.

Elementary analysis:

Calculated for: C I-I 0 C 66.08 H 6.83 Found: C 66.17 H 7.00

EXAMPLE 3 In 100 parts by volume of methanol is added 4.3 parts byweight of 3-(4'-methoxybenzylidene)-2,4-pentanedione. Using 0.3 part byweight of palladium-carbon (5 percent), the mixture is subjected tocatalytic hydrogenation under atmospheric pressure at room temperaturefor minutes. The resultant is crystallized from aqueous ethanol toobtain 2.6 parts by weight of 3-(4-methoxybenzyl)-2,4-pentanedionemelting at -77C as platy crystals.

Elementary analysis:

Calculated for: C H O Found; C 70.81 H 7.32

EXAMPLE 4 In 70 parts by volume of methanol is added 3 parts by weightof 3-(3',4,5'-trimethoxybenzylidene)-2,4-pentanedione, and then themixture is subjected to catalytic hydrogenation under atmosphericpressure at room temperature by using 0.3 part by weight of pa]-ladium-carbon (5 percent). After minutes, the mixture is processed afterthe same manner as in Example 1. The resultant crystallized from amixture of ethyl acetate and n-hexane, whereby 2 parts by weight of 3-(3',4,5-trimethoxybenzyl)-2,4-pentanedione is obtained as crystal. Thecrystals are recrystallized from a mixture of ethyl acetate and n-hexaneto obtain pure crystals melting at 8687C.

Elementary analysis:

Calculated for: C H O Found: C 64.16 H 7.03

EXAMPLE 5 In a mixture of 50 parts by volume of acetic acid and 30 partsby volume of ethyl acetate is dissolved 10 parts by weight of3-(3'-methoxy-4-hydroxybenzylidene)- 2,4-pentanedione under heating. Tothe mixture, 6 parts by weight of zinc dust is added with stirringlittle by little in 20 minutes at room temperature. The resultant issubjected to filtration, and the residue is washed with 30 parts byvolume of ethyl acetate. The washing is combined with the filtrate. Thesolvent is distilled off to leave 10 parts by weight of yellowish oilysubstance. The yellowish oily substance is subjected to columnchromatography on silica gel (50 parts by weight) with a mixture ofbenzene and acetone (30:1) as an eluent. The fraction corresponding tothe desired 3-(3'-methoxy-4'-hydroxybenzyl)-2,4-pentanedione iscollected, and the solvent is distilled off, whereby 6 parts by weightof colorless oily substance is obtained. The substance is crystallizedfrom aqueous ethanol to obtain colorless crystals melting at 75C. Amixed melting of thus obtained product with the product of Example 2does not show lowering of the melting point.

EXAMPLE 6 In 100 parts by volume of a mixture of ethyl acetate andmethanol (1:1) is added 5 parts by weight of 3-(2'-hydroxybenzylidene)-2,4-pentanedione. The mixture is subjected tocatalytic hydrogenation at 24C under atmospheric pressure by usingplatinum oxide. The reaction is finished in 1 hour. The catalyst isfiltered off, and the solvent is distilled off from the filtrate,whereby 5 parts by weight of yellowish oily substance is obtained. Theoily substance is subjected to column chromatography on silica gel (80parts by weight) with a mixture of benzene and ethyl acetate (20:1) asan eluent to obtain 3.0 parts by weight of 3-(2-hydroxybenzyl)-2,4-pentanedione as pale yellowish oil boiling at l6ll62 C(0.7mmHg).

Elementary analysis:

Calculated for: C H O Found: C 69.43 H 6.86

As indicated hereinbefore, the compounds of this invention can beadministered in a variety of composition forms, some examples of whichare as follows:

Composition 1.

What is claimed is: l. The compound 3-(3'-methoxy-4'-hydroxbenzyl)-2,4-pentanedione.

